title: Development and validation of a liquid chromatography-mass spectrometry (LC-MS) assay for the determination of the anti-cancer agent N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049).
abstract: N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent topoisomerase II poison being developed to treat solid tumours. A reliable and sensitive LC-MS method has been developed and validated for the determination of SN 28049 in plasma using a structurally similar internal standard. This method had acceptable intra- and inter-assay accuracy (95-105%) and precision (R.S.D.<6.5%) over the range 0.062-2.5 microM (using a 100 microl sample), and had a lower limit of quantitation of 0.062 microM. Both aqueous and plasma solutions of SN 28049 were stable during short-term (24h at room temperature or 4 degrees C) and long-term storage (8 months at -80 degrees C), and following freezing and thawing (three cycles). The method was applied to study the pharmacokinetics of SN 28049 in mice after iv administration (8.9 mg/kg; n=3 mice per time point). The maximum plasma concentration achieved was 1.22+/-0.05 microM, and concentrations were measurable up to 12h post-administration. A bi-exponential concentration-time curve was observed with an elimination half-life of 2.3+/-0.2h (mean+/-S.E.), a volume of distribution of 34.5+/-2.2l/kg, and a plasma clearance of 12+/-0.5l/h/kg.
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Pradeep B
authors.initials: PB
authors.lastname: Lukka
authors.forename: Philip
authors.initials: P
authors.lastname: Kestell
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods*; D004355:Drug Stability; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D009287:Naphthyridines / Q000032:analysis / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D012015:Reference Standards; D012044:Regression Analysis; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; C533598:N-(2-(dimethylamino)ethyl)-2,6-dimethyl-1-oxo-1,2-dihydroxybenzo(b)-1,6-naphthyridine-4-carboxamide; D009287:Naphthyridines